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B-cell Lymphoma In retrieved Femoral Heads: A Long Term Follow Up
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Eline W Zwitser, MD1, Arthur de Gast, MD, PhD1*, Mirjam J A Basie, B.Sc. (Med)1,
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Folkert J. van Kemenade, MD, PhD2, Barend J van Royen, MD, PhD1
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1Department
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The Netherlands.
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2Department
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The Netherlands.
of Orthopaedic Surgery, VU University Medical Center, Amsterdam,
of Pathology, VU University Medical Center, Amsterdam,
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*Corresponding author
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E-mail addresses:
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EWZ: ewzwits@hotmail.com
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AdG: a.degast@vumc.nl
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MJAB: mbe500@student.vu.nl
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FJvK: f.vkemenade@vumc.nl
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BJvR: bj.vanroyen@vumc.nl
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Abstract
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Background A relative high incidence of pathological conditions in retrieved femoral
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heads, including a group of patients having low grade B-cell lymphoma, have been
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described before. At short term follow up none of these patients with low-grade B-
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cell lymphoma showed evidence of systemic disease. However, the long term follow
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up of these patients is not known.
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Methods From November 1994 up to and including December 2005 we screened all
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femoral heads removed at the time of primary total hip replacement
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histopathologically and included them in the bone banking protocol according to the
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guidelines of the American Associations of Tissue Banks (AATB) and the European
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Association of Musculo-Skeletal Transplantation (EAMST) We determined the
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percentage of B-cell lymphoma in all femoral heads and in the group that fulfilled all
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criteria of the bone banking protocol and report on the long-term follow-up.
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Results Of 852 femoral heads 14 (1.64%) were highly suspicious of low-grade B-cell
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lymphoma. Of these 852 femoral heads 504 were eligible for bone transplantation
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according to the guidelines of the AATB and the EAMST. Six femoral heads of this
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group of 504 were highly suspicious of low-grade B-cell lymphoma (1.19%). At long
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term follow up two (0.23%) of our patients developed systemic malignant disease
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and one of them needed medical treatment for her condition.
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Conclusion In routine histopathological screening we found variable numbers of low-
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grade B-cell lymphoma throughout the years, even in a group of femoral heads that
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were eligible for bone transplantation. Allogenic transmission of malignancy has not
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yet been reported on, but surviving viruses are proven to be transmissible. In addition
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patients with neoplastic histopathological findings need monitoring and follow up.
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Therefore we recommend the routine histopathological evaluation of all femoral
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heads removed at primary hip arthroplasty as a tool for quality control, whether the
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femoral head is used for bone banking or not.
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Key words: B-cell lymphoma, bone allograft, histological examination
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Background
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Allograft donor bone is successfully used in reconstructive tumour surgery and
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revision of total hip arthroplasties [1,2]. Bone banks collect femoral heads according
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to the safety procedures of the American Associations of Tissue Banks (AATB) and
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the European Association of Musculo-Skeletal Transplantation (EAMST) [3,4]. These
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constantly updated guidelines are of the utmost importance in order to prevent the
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transmission of infectious diseases.
Despite these extensive procedures there have been recent publications of
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living cells within donor tissue after routine cryopreservation [5-7]. The potential risk
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of transmission of diseases from donor to recipient by these surviving cells remains
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uncertain, but there have been several reports on the development of infectious
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diseases due to the transplantation of contaminated allograft bone [8-14]. Previously,
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we and another group recommended routine histological examination in the
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screening protocol because of a relative high percentage of pathological conditions in
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retrieved femoral heads, including a group of patients having low grade B-cell
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lymphoma [15,16]. At short term follow up none of the patients with low-grade B-cell
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lymphoma in the femoral head showed evidence of systemic disease. However the
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clinical consequences of these findings remained unknown. Therefore we continued
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our prospective study to screen all retrieved femoral heads after total hip arthroplasty
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histopathologically, including those that were not suitable for bone banking. We
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determined the percentage of B-cell lymphoma in all femoral heads and in the group
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that met all criteria of the bone banking protocol and report on the long-term follow-
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up.
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Patients and methods
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From November 1994 up to and including December 2005 all femoral heads
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removed at the time of primary total hip replacement were collected according to the
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guidelines of the AATB and EAMST [3,4]. All patients gave written and signed
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informed consent. They were screened by a questionnaire in regard to
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their medical, social and sexual history. The questionnaire was based on pre-existing
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forms, followed the guidelines of the AATB and EAMST, and was written in the
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national language; the patients were interviewed by a doctor. In
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addition, a thorough physical and routine blood examination was performed. Blood
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was collected to determine the blood group and Rhesus factor, white blood cell count
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and screening tests were performed to exclude syphilis, HBV and hepatitis C virus
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(HCV), cytomegalovirus (CMV), HIV1 and 2 and HTLV type 1. An increased ESR
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was also used as a criterion for exclusion. All donors were retested for HIV1 and 2,
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syphilis, HBV, HCV and HTLV1 six months after the donation taking into account the
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negative window period.
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After resection of the femoral heads, swabs from bone and capsule were taken for
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aerobic and anaerobic cultures. A core bone biopsy specimen (1 cm3) and a part of
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the capsule were retrieved for histopathological examination. Cores or biopsies were
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in general too big for electrolytical decalcification, as is routine in the laboratory for
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trephine biopsies, but were decalcified in Kirstensen’ solution in a daily controlled
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fashion. After decalcification, biopsies were routinely processed and microscopy was
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performed on Hematoxylin and eosin. In case of suspicion (ie lymphocytic collections
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that were monotoneous) additional stains and immunohistochemistry was performed
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to confirm diagnosis and, if possible, classify.
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Grafts were stored at – 80˚C and 6 months later another blood examination followed.
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We earlier described our bone bank screening procedure in detail [15]
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Femoral heads of patients who were excluded somewhere in this bone banking
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selection process were sent for routine histopathological examination only.
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Non Hodgkin Lymphoma was diagnosed according to routine diagnostic procedures
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in the laboratory by expert hematopathologists. Criteria were an increase in lymphoid
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cells in general variable between interstitial pattern of infiltration, or paratrabecular
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localization of two or more nodules to packed marrow of cells with short chain
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restriction (kappa or Lambda) and uniform B-cell marker (CD20, CD79a, CD23
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expression). In case of concomitant elevated peripheral white blood cell counts, CLL
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was diagnosed.
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We determined the percentage of low-grade B-cell lymphoma in all femoral heads
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and in the group that was suitable according to the bone banking protocol. Patients
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having low-grade B-cell lymphoma in the femoral head were referred to a
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haematologist-oncologist for further evaluation. Follow up of these patients consisted
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of clinical and radiological assessment on a yearly basis, reviewing hospital files and
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contacting family doctors. We assessed if patients had symptoms of systemic
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disease and if they were treated by other physicians.
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Results
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From November 1994 to December 2005 we obtained 852 femoral heads removed at
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the time of primary total hip replacement from 737 patients (205 men, 532 women),
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mean age 69 years (Range 23 to 94 years). We reported earlier on 137 of these
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femoral heads [15]. Fourteen of 852 femoral heads were highly suspicious of low-
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grade B-cell lymphoma (1.64%). These fourteen femoral heads were retrieved from
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13 donors. Mean age of these donors was 67 years (Range 51-79 years)
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Of 852 femoral heads, 504 fulfilled all criteria for donation according to the existing
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guidelines of EAMST and AATB. 348 Femoral heads were discarded, because of
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either a positive donor history (questionnaire), an increased ESR, or positive
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serological, histological or bacterial tests; if malignant disease was diagnosed within
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six months of donation. Some femoral heads have been rejected because of
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incomplete information from the screening tests. Six of 504 allografts were excluded
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based solely on the histopathological features of B-cell lymphoma (1.2%) These 6
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femoral heads were retrieved from 6 different donors. These femoral heads were
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excluded from clinical use and donation.
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We found variable numbers of low-grade B-cell lymphoma throughout the years.
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The distribution of low-grade B-cell lymphoma for each year is shown in figure 1.
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We performed a long term follow up, median follow up 7.2 year (Range 1-12 years)
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In long term follow up one patient developed a B-cell lymphoma in a lymph vessel in
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the inguinal region on the contralateral side, 3 years after the histopathological
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diagnosis low-grade B-cell lymphoma was established. She underwent a lymph node
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excision and started with chemotherapy and radiotherapy. Currently this patient is
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stable (non-progressive disease) for 3 years but still monitored by a haematologist-
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oncologist.
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Another patient developed chronic lymphatic leukaemia. There was no treatment
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indicated, she is under the supervision of a haematologist-oncologist. Three other
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patients are still being controlled on a yearly base by a haematologist, however they
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did not develop malignant disease so far.
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Discussion
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In routine histopathological screening of 852 femoral heads we found 14 low-grade
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B-cell non Hodgkin Lymphoma (NHL) throughout the years. Even in the group of 504
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femoral heads that were eligible for bone transplantation 6 femoral heads were
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suspicious of low-grade B-cell lymphoma. We have performed a long term follow up
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of these 13 patients in which we diagnosed low-grade B-cell NHL in their removed
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femoral heads. Two patients developed systemic malignant disease, one of them
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needed medical treatment for her condition. Three other patients are controlled on a
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yearly base by a haematologist.
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Non-Hodgkin lymphoma (NHL) is a malignancy of the lymphatic system,
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caused by uncontrolled proliferation of B- or T-cell lymphocytes. It is relatively
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uncommon, but the standardized incidence has increased dramatically in the past
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few decades and expected to increase with 36,1% between 2000 and 2020 [17,18].
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Extensive research to assess this increase shows a diversity of potential risk factors,
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such as food, environmental and occupational factors, hair dye, viruses, hepatitis C
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infection, immunosuppression and blood transfusion. However, explanations
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accounting for all increases are not yet available [19-27]. Treatment of patients with
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NHL depends on histological type, clinical stage and prognostic group [28]. In low-
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grade B-cell lymphoma by the time of diagnosis the disease is widespread and
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therefore incurable, but only a small group of patients develops systemic malignant
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disease. Therefore a watch and wait approach is indicated. Palliative chemotherapy
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can be started at the moment the patient presents with systemic manifestation of
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disease [29]. In our study one patient of the 13 diagnosed with B-NHL developed
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systemic malignant disease for which she needed medical treatment. Four other
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patients are being monitored on a yearly base by a haematologist.
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Recent literature questions the necessity of routine histopathological
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examination of retrieved femoral heads. There are studies that find the cost-
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performance ratio of routine histopathological evaluation unfavorable because of the
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little clinical significance in changes of treatment by the diagnoses found [33-37].
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Other studies recommend routine evaluation because of important incidence of
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unsuspected, malignant diagnoses and as a tool for quality control [15,16,38].
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The significance of these diagnoses is still unknown, but patients with
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neoplastic histopathological findings need monitoring and follow up. During this follow
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up two of our patients developed systemic malignant disease and one needed
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medical treatment for her condition. In addition it is not proven that malignant disease
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is not transmissible by allogenic bone transplantation.
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So far, the diagnosis benefited the donors. The implications for the recipients
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are less clear. Allograft bone from osteoarthritic femoral heads is a commonly grafted
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tissue. Cryopreservation at -80 °C for 6 months is a safety standard in order to kill all
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cells present in the femoral heads. There have been recent publications of living cells
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within tissue after routine cryopreservation [5-7]. These living cells can be cultured in
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vitro and are found to originate from the donor. Therefore it is concluded that
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cryopreservation for 6 months does not routinely kill all cells within donor tissue.
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Transmission of a B-NHL cannot be excluded therefore. [30]. So far, there are
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several reports of donor to recipient transmission of infectious diseases by bone
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grafting [8-14], T-cell associated malignancies [31] or EBV associated NHL [39]
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Therefore we recommend the routine histopathological evaluation of all femoral
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heads removed at primary hip arthroplasty as a tool for quality control, whether the
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femoral head is used for bone banking or not.
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Figure 1.
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Distribution of low grade B cell lymphoma found in retrieved femoral heads
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1,5
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number of low grade B cell lymphoma
0,5
0
94
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99 2000 2001 2002 2003 2004 2005
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Competing interests
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The author(s) declare that they have no competing interests.
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Authors' contributions
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All authors have been involved in the development of the study design and research
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protocols. BJvR and AdG participated in the general coordination of the study and
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drafted the manuscript. EWZ and MJAB carried out data collection. FJvK was
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responsible for the pathology. All authors read and corrected draft versions of the
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manuscript and approved the final manuscript.
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